Project Summary/Abstract Musculoskeletal disorders affecting the bones and joints are a growing health problem. Osteoporosis affects over 10 million people in the United States. In addition, bone fractures result in over 3 million emergency department visits a year. Since our ability to treat and prevent these diseases is still very rudimentary, elucidating the mechanisms that regulate bone formation is crucial for understanding the pathologic changes in bone diseases and for developing targeted treatments to increase bone formation. Prior results identified a group of G-protein coupled receptors that are highly expressed in osteoblasts after activation of the Gs-GPCR signaling pathway. One of these receptors, GPR116, is an orphan adhesion GPCR with no previously identified role in bone formation. Preliminary studies indicate that GPR116 can regulate trabecular bone formation. The overall objective of this proposal is to define the roles of GPR116 in the skeleton using a systematic approach in three specific aims: 1) identify the signaling pathways activated by GPR116; 2) determine the physiologic role of GPR116 in osteoblasts using a tissue-specific knockout mouse model; and 3) determine if GPR116 regulates the formation of cartilage or bone using a human induced pluripotent stem (iPS) cell model system. Successful completion of these studies will identify the roles of GPR116 in regulating trabecular bone formation and contribute to our understanding about the function of adhesion GPCRs. The results will establish a strong framework for future studies including how GPR116 regulates skeletal tissue formation, tumor metastasis, or ectopic bone formation. The proposed research is part of a coordinated career development plan to prepare the candidate to be an outstanding, independent physician-scientist. At the end of this award, the results and reagents from this study will be used by the candidate to apply for an independent investigator award such as the NIH R01 grant.